Expression of CD44v6 is an independent prognostic factor for poor survival in patients with esophageal squamous cell carcinoma

Shiozaki, Midori; Ishiguro, Hideyuki; Kuwabara, Yoshiyuki; Kimura, Masahiro; Mitsui, Akira; Naganawa, Yasuhiro; Shibata, Takahiro; Fujii, Yoshitaka; Takeyama, Hiromitsu

doi:10.3892/ol.2011.264

Cited by 6 publications

(3 citation statements)

References 29 publications

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“…Gene expression analysis (GSE37993) further indicated downregulation of epithelial splicing regulatory protein (ESRP)1 (−29.0-fold vs. CD44L; p<0.001) and ESRP2 (−5.4-fold vs. CD44L; p<0.001), which regulate alternative splicing of CD44 mRNA 55 , in purified CD44H cells. As CD44v6 expression has been implicated in ESCC, 39 , 49 , 57 we continued to examine its expression in the context of keratinocyte EMT. Indeed, both CD44H cells ( Supplementary Figure S6C–E ) and TGF-β-treated CD44L ( Supplementary Figure S7 ) cells displayed decreased cell surface CD44v6 protein expression.…”

Section: Resultsmentioning

confidence: 99%

Autophagy supports generation of cells with high CD44 expression via modulation of oxidative stress and Parkin-mediated mitochondrial clearance

et al. 2017

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High CD44 expression is associated with enhanced malignant potential in esophageal squamous cell carcinoma (ESCC), amongst the deadliest of all human carcinomas. Although alterations in autophagy and CD44 expression are associated with poor patient outcomes in various cancer types, the relationship between autophagy and cells with high CD44 expression remains incompletely understood. In transformed esophageal keratinocytes, CD44Low-CD24High (CD44L) cells give rise to CD44High-CD24−/Low (CD44H) cells via epithelial-mesenchymal transition (EMT) in response to transforming growth factor (TGF)-β. We couple patient samples and xenotransplantation studies with this tractable in vitro system of CD44L to CD44H cell conversion to investigate the functional role of autophagy in generation of cells with high CD44 expression. We report that high expression of the autophagy marker cleaved LC3 expression correlates with poor clinical outcome in ESCC. In ESCC xenograft tumors, pharmacological autophagy inhibition with chloroquine derivatives depletes cells with high CD44 expression while promoting oxidative stress. Autophagic flux impairment during EMT-mediated CD44L to CD44H cell conversion in vitro induces mitochondrial dysfunction, oxidative stress and cell death. During CD44H cell generation, transformed keratinocytes display evidence of mitophagy, including mitochondrial fragmentation, decreased mitochondrial content and mitochondrial translocation of Parkin, essential in mitophagy. RNA interference-mediated Parkin depletion attenuates CD44H cell generation. These data suggest that autophagy facilitates EMT-mediated CD44H generation via modulation of redox homeostasis and Parkin-dependent mitochondrial clearance. This is the first report to implicate mitophagy in regulation of tumor cells with high CD44 expression, representing a potential novel therapeutic avenue in cancers where EMT and CD44H cells have been implicated, including ESCC.

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Section: Resultsmentioning

confidence: 99%

Autophagy supports generation of cells with high CD44 expression via modulation of oxidative stress and Parkin-mediated mitochondrial clearance

et al. 2017

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“…Several studies have demonstrated the overexpression of CD44v6 in several cancers, including but not limited to head and neck, breast, ovarian, prostate, colon and colorectal cancer ( 6 – 11 ), whereas CD44v6 expression in normal tissue is restricted to the squamous and transitional epithelium ( 12 , 13 ). Additionally, the overexpression of CD44v6 is associated with a poor prognosis and a more aggressive, chemoresistant disease in several cancer types ( 7 – 9 , 14 – 18 ). In metastatic tissue, a retained or increased CD44v6 expression compared to primary tumors has been demonstrated in certain types of cancer, such as squamous cell carcinomas, prostate cancer and ovarian cancer ( 7 , 9 , 19 , 20 ), whereas studies on colorectal cancers have reported heterogeneous results ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy

et al. 2018

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CD44v6 is overexpressed in a variety of cancers, rendering it a promising target for radio-immunotherapy (RIT). In this study, we have characterized a novel engineered recombinant monoclonal anti-CD44v6 antibody, AbN44v6, and assessed its potential for use in RIT using either 177Lu or 131I as therapeutic radionuclides. In vitro affinity and specificity assays characterized the binding of the antibody labeled with 177Lu, 125I or 131I. The therapeutic effects of 177Lu-AbN44v6 and 131I-AbN44v6 were investigated using two in vitro 3D tumor models with different CD44v6 expression. Finally, the normal tissue biodistribution and dosimetry for 177Lu-AbN44v6 and 125I-AbN44v6/131I-AbN44v6 were assessed in vivo using a mouse model. All AbN44v6 radioconjugates demonstrated CD44v6-specific binding in vitro. In the in vitro 3D tumor models, dose-dependent therapeutic effects were observed with both 177Lu-AbN44v6 and 131I-AbN44v6, with a greater significant therapeutic effect observed on the cells with a higher CD44v6 expression. Biodistribution experiments demonstrated a greater uptake of 177Lu-AbN44v6 in the liver, spleen and bone, compared to 125I-AbN44v6, whereas 125I-AbN44v6 demonstrated a longer circulation time. In dosimetric calculations, the critical organs for 177Lu-AbN44v6 were the liver and spleen, whereas the kidneys and red marrow were considered the critical organs for 131I-AbN44v6. The effective dose was in the order of 0.1 mSv/MBq for both labels. In conclusion, AbN44v6 bound specifically and with high affinity to CD44v6. Furthermore, in vitro RIT demonstrated growth inhibition in a CD44v6-specific activity-dependent manner for both radioconjugates, demonstrating that both 177Lu-AbN44v6 and 131I-AbN44v6 may be promising RIT candidates. Furthermore, biodistribution and dosimetric analysis supported the applicability of both conjugates for RIT. The CD44v6-specific therapeutic effects observed with radiolabeled AbN44v6 in the 3D tumor models in vitro, combined with the beneficial dosimetry in vivo, render AbN44v6 a potential candidate for RIT.

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“…Specifically, overexpression of the CD44v6 variant has been found in the majority of squamous cell carcinomas and a variety of adenocarcinomas, but has not frequently been observed in non-epithelial tumors ( 18 ). In this way, CD44v6 has been described to negatively impact the prognosis of patients with multiple myeloma ( 19 ), colorectal cancer (CRC) ( 20 , 21 ), osteosarcoma ( 22 ), esophageal carcinoma ( 22 ), gastric cancer ( 23 ) as well as head and neck squamous cell carcinoma (HNSCC) ( 24 , 25 ) patients, among others. Moreover, altered CD44v6 expression has been associated with tumor development, migration, invasion and metastatic potential in a broad variety of tumor types, such as HNSCC ( 24 ), oral cancer ( 26 ), laryngeal carcinoma ( 27 ), esophageal squamous cell carcinoma, gastric cancer ( 28 – 30 ), pancreatic cancer ( 11 , 31 ), liver cancer ( 32 , 33 ), CRC ( 34 ), lung cancer ( 35 , 36 ), breast carcinoma ( 37 ) and gynecologic malignancies ( 38 ) such as ovarian ( 39 , 40 ) and prostate cancer ( 41 ), among others ( Figure 1 ).…”

Section: Cd44 Alternative Splicing As a Source Of Taasmentioning

confidence: 99%

CD44v6, STn & O-GD2: promising tumor associated antigens paving the way for new targeted cancer therapies

Lodewijk,

Dueñas,

Paramio

et al. 2023

Front. Immunol.

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Targeted therapies are the state of the art in oncology today, and every year new Tumor-associated antigens (TAAs) are developed for preclinical research and clinical trials, but few of them really change the therapeutic scenario. Difficulties, either to find antigens that are solely expressed in tumors or the generation of good binders to these antigens, represent a major bottleneck. Specialized cellular mechanisms, such as differential splicing and glycosylation processes, are a good source of neo-antigen expression. Changes in these processes generate surface proteins that, instead of showing decreased or increased antigen expression driven by enhanced mRNA processing, are aberrant in nature and therefore more specific targets to elicit a precise anti-tumor therapy. Here, we present promising TAAs demonstrated to be potential targets for cancer monitoring, targeted therapy and the generation of new immunotherapy tools, such as recombinant antibodies and chimeric antigen receptor (CAR) T cell (CAR-T) or Chimeric Antigen Receptor-Engineered Natural Killer (CAR-NK) for specific tumor killing, in a wide variety of tumor types. Specifically, this review is a detailed update on TAAs CD44v6, STn and O-GD2, describing their origin as well as their current and potential use as disease biomarker and therapeutic target in a diversity of tumor types.

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Expression of CD44v6 is an independent prognostic factor for poor survival in patients with esophageal squamous cell carcinoma

Cited by 6 publications

References 29 publications

Autophagy supports generation of cells with high CD44 expression via modulation of oxidative stress and Parkin-mediated mitochondrial clearance

Autophagy supports generation of cells with high CD44 expression via modulation of oxidative stress and Parkin-mediated mitochondrial clearance

Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy

CD44v6, STn & O-GD2: promising tumor associated antigens paving the way for new targeted cancer therapies

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